The impact of proliferating mast cells in the developing brain

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Project Summary Both resident and peripheral immune cells are increasingly implicated in the pathophysiology of various neurodevelopmental disorders, including autism, but the mechanisms by which these non-neuronal cells impact the brain is largely unknown. Infiltrating immune cells in the brain readily respond to environmental triggers, promoting persistent proinflammatory signaling that permanently alters developing cells and damages non- renewing populations. The resident immune cells of the brain, microglia, regulate normal physiologic processes to guide brain development, but little is known about the contribution of infiltrating immune cells to these same processes. In my preliminary studies, I found thousands of mast cells, a component of the innate immune system, inhabiting the lateral ventricles adjacent the hippocampus, throughout perinatal stages of brain development. This raises the question – what role might such proinflammatory cells serve in the developing brain? Mast cells (MC) are both highly sensitive to a variety of stimuli and reflexively produce a wide assortment of vasoactive molecules, cytokines, and growth factors, making them a potential neuro-immune hub during neurodevelopment. Moreover, since mast cells are so exquisitely responsive to inflammatory signals, they may serve dual functions: potentially supporting cell genesis and maturation, or perpetrating damage. This proposal seeks to address gaps in our understanding of MC recruitment, heterogeneity, and function in the developing brain to assess how this population may contribute to neurodevelopmental disorders. We have shown, for the first time, that brain MC are replicating along the hippocampal fissure and are maintained in this region for the first two postnatal weeks, paralleling neurogenesis and microglial maturation occurring nearby. Advanced flow cytometric techniques will test the hypothesis that they are locally proliferating, which MC do not typically do outside of the bone marrow (Aim 1.1). To elucidate their functional and molecular identity in the developing CNS, we will perform single cell RNA-sequencing of brain MCs and compare their transcriptome to prototypical MCs from the skin and bone marrow (Aim 1.2). Findings from transcriptomic analyses will guide exploration of their mechanism of influence on typical developmental processes in the hippocampus. Lastly, MC are well known to coordinate with microglia in the injured adult brain, but this relationship has not been thoroughly explored during development. We will test our hypothesis that MCs release signaling factors that promote microglial maturation in the hippocampus (Aim 2). These findings will reframe understanding of the developing brain as an immune-enabled site requiring nuanced neuro-immune interactions to sustain developmental processes. This project fosters training in bioinformatics and immersion in two historically independent fields to prepare me for a career investigating neural-immune communication in health and disease. Scientific mentorship from neuroscientist Dr. Margaret McCarthy and immunologist Dr. Nevil Singh, paralleled by clinical mentorship from neuroimmunologist Dr. David Benavides, will establish a strong foundation for my life as a physician-scientist in the field of child neurology.